Use Of PD-1 Inhibitors Research Articles

Risk factors and outcomes of pericardial effusion in cancer patients receiving PD-1 inhibitors

BackgroundProgrammed cell death 1 (PD-1) inhibitors can induce various adverse reactions associated with immunity, of which cardiotoxicity is a serious complication. Limited research exists on the link between PD-1 inhibitor use and pericardial effusion (PE) occurrence and outcomes. MethodsWe conducted a retrospective study at the First Affiliated Hospital of Xi'an Jiaotong University from 2017 to 2019, comparing cancer patients who developed PE within 2 years after PD-1 inhibitor therapy to those who did not. Our primary outcome was the all-cause mortality rate at one year. We applied the Kaplan-Meier method for survival analysis. Multivariate logistic regression was utilized to identify PE risk factors, adjusting for potential confounders. ResultsA total of 91 patients were finally included, of whom 39 patients had PE. Compared to non-PE group, one-year all-cause mortality was nearly 5 times higher in PE group (64.10% vs. 13.46%, P < 0.001). Patients who developed PE within 2 years of taking PD-1 inhibitors were significantly associated with increased all-cause mortality compared with those who did not (HR: 6.26, 95%CI: 2.70–14.53, P < 0.001). Multivariable logistic regression showed that use of sintilimab (OR: 14.568, 95%CI: 3.431–61.857, P < 0.001), history of lung cancer (OR: 15.360, 95%CI: 3.276–72.017, P = 0.001), and history of hypocalcemia (OR: 7.076, 95%CI: 1.879–26.649, P = 0.004) were independent risk factors of PE development in patients received PD-1 inhibitors therapy. ConclusionsIn cancer patients receiving PD-1 inhibitors, PE was associated with higher one-year mortality. Use of sintilimab, and history of lung cancer or hypocalcemia were linked to PE occurrence.

Construction of an immune-related gene signature for overall survival prediction and immune infiltration in gastric cancer.

Treatment options for patients with gastric cancer (GC) continue to improve, but the overall prognosis is poor. The use of PD-1 inhibitors has also brought benefits to patients with advanced GC and has gradually become the new standard treatment option at present, and there is an urgent need to identify valuable biomarkers to classify patients with different characteristics into subgroups. To determined the effects of differentially expressed immune-related genes (DEIRGs) on the development, prognosis, tumor microenvironment (TME), and treatment response among GC patients with the expectation of providing new biomarkers for personalized treatment of GC populations. Gene expression data and clinical pathologic information were downloaded from The Cancer Genome Atlas (TCGA), and immune-related genes (IRGs) were searched from ImmPort. DEIRGs were extracted from the intersection of the differentially-expressed genes (DEGs) and IRGs lists. The enrichment pathways of key genes were obtained by analyzing the Kyoto Encyclopedia of Genes and Genomes (KEGGs) and Gene Ontology (GO) databases. To identify genes associated with prognosis, a tumor risk score model based on DEIRGs was constructed using Least Absolute Shrinkage and Selection Operator and multivariate Cox regression. The tumor risk score was divided into high- and low-risk groups. The entire cohort was randomly divided into a 2:1 training cohort and a test cohort for internal validation to assess the feasibility of the risk model. The infiltration of immune cells was obtained using 'CIBERSORT,' and the infiltration of immune subgroups in high- and low-risk groups was analyzed. The GC immune score data were obtained and the difference in immune scores between the two groups was analyzed. We collected 412 GC and 36 adjacent tissue samples, and identified 3627 DEGs and 1311 IRGs. A total of 482 DEIRGs were obtained. GO analysis showed that DEIRGs were mainly distributed in immunoglobulin complexes, receptor ligand activity, and signaling receptor activators. KEGG pathway analysis showed that the top three DEIRGs enrichment types were cytokine-cytokine receptors, neuroactive ligand receptor interactions, and viral protein interactions. We ultimately obtained an immune-related signature based on 10 genes, including 9 risk genes (LCN1, LEAP2, TMSB15A mRNA, DEFB126, PI15, IGHD3-16, IGLV3-22, CGB5, and GLP2R) and 1 protective gene (LGR6). Kaplan-Meier survival analysis, receiver operating characteristic curve analysis, and risk curves confirmed that the risk model had good predictive ability. Multivariate COX analysis showed that age, stage, and risk score were independent prognostic factors for patients with GC. Meanwhile, patients in the low-risk group had higher tumor mutation burden and immunophenotype, which can be used to predict the immune checkpoint inhibitor response. Both cytotoxic T lymphocyte antigen4+ and programmed death 1+ patients with lower risk scores were more sensitive to immunotherapy. In this study a new prognostic model consisting of 10 DEIRGs was constructed based on the TME. By providing risk factor analysis and prognostic information, our risk model can provide new directions for immunotherapy in GC patients.

The occurrence of immune-related adverse events is an independent risk factor both for serum HBsAg increase and HBV reactivation in HBsAg-positive cancer patients receiving PD-1 inhibitor combinational therapy.

Previous studies have suggested the potential of PD-1/PD-L1 inhibitors in the treatment of chronic HBV infection. However, since phase III clinical trials have not yet been announced, additional clinical insights may be obtained by observing changes in serum hepatitis B surface antigen (HBsAg) and HBV-DNA levels in cancer patients undergoing PD-1 inhibitor therapy. To explore the effects of PD-1 inhibitor combinational therapy on serum HBsAg and HBV-DNA levels, investigate the incidence of HBsAg loss, HBV reactivation (HBVr), and immune-related adverse events (irAEs), and identify the risk factors associated with significant HBsAg fluctuations and HBVr. A retrospective study including 1195 HBsAg-positive cancer patients who received PD-1 inhibitors between July 2019 and June 2023 was conducted, and 180 patients were enrolled in this study. Serum HBsAg levels before and after PD-1 inhibitor administration were compared across different subgroups. The Pearson χ2 or Fisher exact test was performed to investigate the relationships between categorical variables. Univariable and multivariable analysis were performed to identify the risk factors associated with significant HBsAg fluctuations and HBVr. With the concurrent use of antiviral agents, serum HBsAg levels decreased (Z=-3.966, P < 0.0001) in 129 patients and increased (t=-2.047, P=0.043) in 51 patients. Additionally, 7 patients (3.89%) achieved serum HBsAg loss. Virus replication was suppressed in most of the enrolled patients. When divided patients into different subgroups, significant HBsAg decreases after PD-1 inhibitor administration were discovered in lower baseline HBsAg group (Z=-2.277, P=0.023), HBeAg-seronegative group (Z=-2.200, P=0.028), non-irAEs occurrence group (Z=-2.007, P=0.045) and liver cancer group (Z=-1.987, P=0.047). Of note, 11 patients and 36 patients experienced HBVr (6.11%) and irAEs (20%), respectively, which could lead to discontinuation or delayed use of PD-1 inhibitors. After multivariable analysis, HBeAg-seropositive (OR, 7.236 [95% CI, 1.757-29.793], P=0.01) and the occurrence of irAEs (OR, 4.077 [95% CI, 1.252-13.273], P=0.02) were identified as the independent risk factors for significant HBsAg increase, the occurrence of irAEs (OR, 5.560 [95% CI, 1.252-13.273], P=0.01) was identified as the only independent risk factor for HBVr. PD-1 inhibitors combined with nucleos(t)ide analogues (NAs) may exert therapeutic potential for chronic HBV infection in cancer patients. However, attention also should be paid to the risk of significant elevation in HBsAg levels, HBVr, and irAEs associated with PD-1 inhibitor combinational therapy.

Lichenoid dermatitis following PD-1 inhibitor-induced toxic epidermal necrolysis: a case report and literature review.

Immune checkpoint inhibitorssuch as anti-PD-1receptor antibodies have been shown to be effective in patients with advanced gastric cancer. However, there is a growing concern about immune-related adverse events. A case of a patient with gastric adenocarcinoma who developed toxic epidermal necrolysis (TEN) induced by sintilimab and subsequently developed lichenoid dermatitis is reported. TEN was diagnosed according to a history of sintilimab use, clinical symptomsand physical examination. During hospitalization, the patient developed recurrent fever caused by bacteremia and recovered from TEN after anti-infection and anti-inflammatory treatments. However, when TEN was controlled, the patient developed the lesional manifestations of lichenoid dermatitis. To date, no cases of lichenoid dermatitis after TEN have been reported following the use of PD-1 inhibitors.

Clinical Characteristics of Aggressive NK-Cell Leukemia

To explore and summarize the clinical characteristics and treatment of aggressive NK-cell leukemia (ANKL), and provide new insights for clinical diagnosis and treatment of this disease. The clinical data of 7 patients with ANKL admitted to the First Affiliated Hospital of Wannan Medical College from March 2014 to July 2021 were retrospectively analyzed, and their clinical characteristics, laboratory and imaging results, treatment and outcomes were analyzed. Among the 7 patients, 5 were males and 2 were females, with a median age of 47 (33-69) years old. The morphology of bone marrow cells in 7 patients showed similar large granular lymphocytes. Immunophenotyping revealed abnormal NK cells in 5 cases. By the end of follow-up, 6 cases died and 1 case survived, with a median survival time of 76.9 (4-347) days. ANKL is a rare disease with short course and poor prognosis. If combined with hemophagocytic syndrome (HPS), the prognosis is even worse. There is no unified treatment method at present, and the use of PD-1 inhibitors may prolong the survival in some patients.

Does it fit in your pocket? economic burden of PD-1 inhibitors' toxicity in the supplementary health system: evidence from Brazil

BackgroundA full understanding of the economic burden associated with treatment-related adverse events (AEs) can aid estimates of the incremental costs associated with incorporating new technologies and support cost-effective economic modeling in Brazil. In this context, the main objective of this work was to evaluate in a real-life database: (i) the direct medical cost of monitoring the occurrence of AEs (CMO); (ii) the direct medical cost of managing an identified AE (CMN); and (iii) the total direct medical cost of monitoring and managing AEs (TMC), in quarterly periods from 0 to 24 months of the monitoring of cancer patients who used a PD-1 inhibitor from the perspective of the supplementary health system in Brazil.MethodsThis study was conducted from the supplementary health system (SSS) perspective and followed the methodological guidelines related to cost-of-illness studies. A bottom-up (person-based) approach was used to assess the use of health resources to monitor and manage AEs during the use of PD-1 inhibitors, which made it possible to capture differences in the mean frequency of the use of health services with stratification results for different subgroups. As the Brazilian SSS is complex, asymmetric, and fragmented, this study used information from different sources. The methodology was divided into three parts: (i) Data Source: clinical management of AEs; (ii) Microcosting: management of the economic burden of AEs; (iii) Statistical analysis: stratification of results for different subgroups.ResultsAnalysis of the economic burden of toxicity showed higher CMO costs than CMN in all the periods analyzed. In general, for every BRL 100 on average invested in the TMC of AEs, BRL 95 are used to monitor the occurrence of the AE and only BRL 5 to manage an identified AE. This work also showed that the sociodemographic characteristics of patients, the journey of oncological treatment, and the toxicity profile affect the economic burden related to AE.ConclusionThis study provided real-world evidence of the economic burden of AEs associated with the use of PD-1 inhibitors in Brazil. This work also made methodological contributions by evaluating the economic burden of AE of PD-1 inhibitors considering the kinetics of toxicity occurrence and categorizing the costs in terms of CMO, CMN and TMC.

Global dynamics of a tumor-immune model with an immune checkpoint inhibitor

In this paper, a mathematical ordinary differential tumor-immune model is proposed based on an immune checkpoint inhibitor, which is an innovative method for tumor immunotherapies. Two important factors in tumor-immune response are the programmed cell death protein 1 (PD-1) and its ligand PD-L1. The model consists of three populations: tumor cells, activated T cells and anti-PD-1. By analyzing the dynamics of the model, it is found that there is always a unique tumor-free equilibrium and at most two tumor interior equilibria. The nonexistence of nontrivial positive periodic orbits is established by using the new Dulac function, and then a global dynamics of the model is obtained. The conclusions of our analysis show that increasing the possibility of T cells killing tumor cells ([Formula: see text]), early detection of tumor cells, or the use of PD-1 inhibitors to activate T cells are effective in eliminating tumor cells.

Cardiovascular risks of chemo-immunotherapy for lung cancer: A population-based cohort study

ObjectivesDespite their proven efficacy for treating lung cancer, the cardiovascular risks associated with programmed cell death protein 1 (PD-1) inhibitors and their combinations with chemotherapy (chemo-immunotherapy) are unclear. This study aimed to investigate these associations. Materials and methodsThis retrospective cohort study included Hong Kong patients with lung cancer receiving PD-1 inhibitors during 2013–2021. Patients with non-concurrent use of PD-1 inhibitors and chemotherapy, any use of tyrosine kinase inhibitors or other immunotherapy agents, and those with prior stroke, heart failure, or myocardial infarction were excluded. PD-1 inhibitors and chemo-immunotherapy were compared for major adverse cardiovascular events (MACE), a composite of cardiovascular mortality, heart failure, stroke, and myocardial infarction. All patients were followed up until the end of 2021. Inverse probability of treatment weighting was used to balance covariates between the two treatment groups. ResultsIn total, 713 patients (333 PD-1 inhibitors users and 380 chemo-immunotherapy users) were analysed. Over a mean follow-up of 1.4 ± 1.3 years, 24 had MACE, with an observed incidence of 2.8 [1.6–4.8] events per 100 person-year for patients on PD-1 inhibitors, and 2.1 [1.2–3.8] per 100 person-year for patients on chemo-immunotherapy. No significant between-group difference in MACE incidence was observed (log-rank p = 0.641). ConclusionThe cardiovascular risks associated with PD-1 inhibitors and chemo-immunotherapy may not be significantly different amongst patients with lung cancer. Cardiovascular events associated with either regimen may be uncommon.

American Head and Neck Society position statement on the use of PD-1 inhibitors for treatment of advanced cutaneous squamous cell carcinoma.

A position statement put forth by the American Head and Neck Society (AHNS) was constructed to provide evidence-based treatment recommendations for PD-1 inhibitor use in advanced cutaneous squamous cell carcinoma (cSCC). Secondarily, we sought to identify knowledge gaps warranting further investigation. A literature search utilizing key terms: cutaneous squamous cell carcinoma, cutaneous cancer, checkpoint inhibitors, systemic therapy, Program Cell Death, PD-1 (PubMed, Cochrane, and Google Scholar) was carried out to generate evidence-based statements. The statements were distributed among the AHNS membership. Delphi methodology was applied to identify statements achieving 70% or greater consensus among the leadership team. Twenty-six position statements achieved consensus. Knowledge gaps for future research included: impact of immunosuppression on cSCC staging and associated treatment; role of PD-1 inhibitors in immunosuppressed patients. This comprehensive position statement put forth by the AHNS represents majority consensus by practicing head and neck surgeons throughout the country.

MA14.08 Longitudinal Symptoms and Health Utility Scores (HUS) in Patients Receiving PD-1 Inhibitors for Metastatic NSCLC

The use of PD-1 inhibitors has dramatically prolonged survival in patients with metastatic NSCLC. Quality of life was better compared to chemotherapy in prospective trials. However, the symptom trajectory over time is not well described, especially for patients who remain on treatment long term. Therefore, we sought to characterize the symptom burden longitudinally in a large population-based sample.

34193 Psoriasiform eruption after treatment with pembrolizumab

Immune checkpoint inhibitors, such as the programmed cell death protein 1 (PD-1) inhibitors, are gaining popularity in the treatment of several types of cancer, and function by stimulating the immune system’s antitumor activity. Immune-related adverse events are common following the use of immune checkpoint inhibitors with rash being the most frequent complaint. Herein, we present the case of a 67-year-old woman with a history of plaque psoriasis and metastatic squamous cell carcinoma of the lung who presented with widespread well-defined erythematous scaly plaques following a dose increase of pembrolizumab (a PD-1 inhibitor).While cutaneous adverse events are common with the use of PD-1 inhibitors, they most frequently manifest as morbilliform eruptions.

Influence of Antibiotic Use on the Effectiveness and Safety of Immune Checkpoint Inhibitors

It has been reported that antibiotic (ATB) use changes the gut microbiome and alters the outcome of treatment with immune checkpoint inhibitors (ICIs). In this retrospective, single-center cohort study, we investigated the effects of concurrent use of PD-1 inhibitors and medications known to modify the gut microbiome including ATBs on the clinical benefit or safety of PD-1 inhibitors across types of cancer in Japanese patients. In total, 143 patients were analyzed: 53 patients received systemic ATBs within 2 months before or 1 month after the first dose of PD-1 inhibitors (the ATB group); the remaining patients comprised the non-ATB group. There was a significantly higher proportion of patients under 65 years of age in the ATB group. Progression-free survival (PFS) in the ATB group was significantly shorter than that in the non-ATB group across types of cancer (HR = 1.82). It is suggested that anti-anaerobic ATBs may be associated with worse PFS. The higher disease control rate was associated with the non-ATB group compared with the ATB group. A multivariate Cox proportional hazard model constructed with PFS showed that the impact of ATBs remained significant for PFS and probiotic use was detected as another independent factor involved in shorter PFS. There were similar frequencies and conditions between the two groups in the incidence of adverse events of Grade 3 or above, and laboratory data. Our results suggest that the use of ATBs may negatively affect the anticancer treatment outcomes of Japanese patients who are administered PD-1 inhibitors.

Lichen planus pemphigoides: A unique form of bullous and lichenoid eruptions secondary to nivolumab.

The widespread use of PD‐1 inhibitors to treat various solid tumors has brought certain challenges for the clinician, including immune‐related adverse events (irAEs). Cutaneous toxicities are among the most observed irAEs. Bullous and lichenoid dermatoses following PD‐1 inhibitor therapy have been described. Here we report a novel case of lichen planus pemphigoides, featuring characteristics of both bullous pemphigoid and lichen planus, in a patient treated with nivolumab for renal cell carcinoma. We subsequently review all three cutaneous conditions which may arise in the context of PD‐1 inhibitor therapy.

Adjunctive PD-1 inhibitor versus standard chemotherapy in recurrent or metastatic nasopharyngeal carcinoma: a systematic review and meta-analysis.

To investigate whether Adjunctive PD-1 inhibitors have improved clinical outcomes compared to chemotherapy alone in platinum-pretreated and platinum-naive recurrent or metastatic nasopharyngeal carcinoma (R/M NPCA). The study involved a literature search from PubMed, Cochrane CENTRAL, and Google Scholar for randomized clinical trials (RCTs) on the use of PD-1 inhibitors versus chemotherapy alone in patients with R/M NPCA. Bias was assessed using Cochrane collaboration's risk of bias tool. Overall Survival (OS) was examined as the primary endpoint. Secondary endpoints were Progression-Free Survival (PFS), Objective Response Rate, Disease Control Rate (DCR), Duration of Response, and Serious/Grade ⩾3 Adverse Events. Outcomes were measured with either Mean Difference, Risk ratio (RR), or Hazard ratios (HRs) at 95% confidence interval. Four RCTs were included in the meta-analysis and systematic review. OS for the monotherapy subgroup was a HR of 0.87 [0.67, 1.13] (p = 0.30) while the combination subgroup had 0.64 [0.45, 0.90] (p = 0.01). The monotherapy subgroup exhibited significantly worse outcomes in PFS (HR 1.31 [1.01, 1.68]) (p = 0.04) and DCR (RR 1.52 [1.12, 2.05]) (p = 0.007) but no significant difference in other outcomes. For combination therapy, a statistically significant benefit can be seen in all outcomes except DCR (RR 0.62 [0.38, 1.01]) (p = 0.06) which was a non-significant benefit favoring PD-1 inhibitors. Combination PD-1 inhibitor + chemotherapy followed by maintenance PD-1 inhibitor therapy is superior to chemotherapy alone in the first-line treatment of R/M NPCA, implying a potential benefit with the use of PD-1 inhibitors + chemotherapy with maintenance PD-1 inhibitors as first-line in R/M NPCA compared to standard chemotherapy alone.

Pharmacological, Technological, and Digital Innovative Aspects in Rhinology.

Innovation refers to the introduction of a product, a process, a service or a solution resulting in something new or significantly improved compared to the already available alternatives. In the clinical context, it is strictly related to the identification of a new added value in terms of quality, therapeutic efficacy and safety. Over the years several innovative approaches have been introduced in the clinical practice, revolutionizing the treatment and the management of important rhinologic conditions. Innovative tools, including new drugs, biomaterials, and mobile applications seem to be able to improve the clinical outcomes and the quality of life of many patients affected by (often relapsing) rhinologic diseases. Among the main modern pharmacological innovations, mention must be made of the biological drugs like monoclonal antibodies (mAbs). Recently, new mAbs have been introduced and investigated as useful arms in the treatment of some inflammatory/infectious or oncological diseases affecting the nasal cavities and paranasal sinuses. The already approved or still investigated mAbs work inhibiting different type 2 inflammation pathways, including those mediated by IgE (omalizumab), IL-4/IL-13 (dupilumab), and IL-5 (mepolizumab). Moreover, considering the higher expression of PD-L1 in nasopharyngeal carcinoma, the use of PD-1 inhibitors, such as nivolumab, or a dual CTLA-4/PD-1 blockade (ipilimumab plus nivolumab) appear to be an effective strategy for the treatment of this cancer form. The implants with bio-absorbable biomaterials represent new interesting available technological innovations. Moreover, advanced technologies such as the artificial intelligence, the machine learning as well as the augmented or virtual reality have also proved useful in rhinologic field with main impacts on precision medicine and surgery. Finally, the development and use of mobile-Health tools represent a winning strategy in monitoring of the therapy success, safety and tolerability as well as the progress of chronic disease including chronic rhinosinusitis with nasal polyps. Supporting the research of innovative tools and strategies (including pharmacological, technologic, or digital ones) is essential to improve the management of chronic diseases that significantly affect the patients' quality of life.

Use of PD-1 Inhibitors in the Treatment of Advanced Basal Cell Carcinoma.

Use of PD-1 Inhibitors in the Treatment of Advanced Basal Cell Carcinoma.

25686 Variability in the dosing of PD1 inhibitors used for treatment of nonmelanoma skin cancers

Nonmelanoma skin cancer (NMSC) represents the most common cancer diagnosed in the United States. These tumors are frequently treated by surgical modalities. Patients with advanced disease require a different approach to therapy. Programmed cell death protein 1 (PD1) inhibitors are an emerging immunotherapeutic option for the treatment of a variety of tumors including advanced NMSC. Cemiplimab is a PD-1 inhibitor approved for treatment of locally advanced or metastatic cutaneous squamous cell carcinoma (cSCC) not amenable to curative surgery or radiation. Pembrolizumab and nivolumab are PD1 inhibitors used as off-label therapies for advanced cSCC or basal cell carcinoma (BCC). We conducted a PubMed literature search up to August 8, 2020 to include studies on the use of PD-1 inhibitors in patients with advanced NMSC. Thirty-seven articles reported a total of 432 unique cases of advanced cSCC or BCC treated with PD1 inhibitors. The most common dosing schedules for pembrolizumab (2 mg/kg q3 weeks), nivolumab (3 mg/kg q2 weeks), or cemiplimab (3 mg/kg q2 weeks) were identified. A total of 10 different dosing schedules were identified. Outcomes of these patients ranged between progressive disease to achievement of a complete clinical response. All 3 PD1 inhibitors showed adequate safety profiles with few reported adverse events that were grade 3 or above. The use of cemiplimab, pembrolizumab, and nivolumab for advanced NMSC has shown promising results. However, the literature shows a wide range of dosing regimens for these therapies. Further studies are needed to guide clinicians toward the optimal dosage and the ideal anti-PD1 agent for their patients.

The incidence of gastrointestinal adverse events in patients with advanced non-small cell lung cancer (NSCLC) treated with PD-1 inhibitors: a meta-analysis

BackgroundWe conducted a meta-analysis to evaluates the incidence of the gastrointestinal (GI) adverse events with the use of PD-1 inhibitors among patients with advanced non-small cell lung cancer (NSCLC).MethodsThe PICOs (participants, intervention, comparison, and outcomes) elements were used for the selection of studies to meet the inclusion and exclusion criteria. Google Scholar, PubMed, Science Direct and proceedings of major oncology conferences were systematically searched from their inception to December 2020, to identify studies which reported the GI adverse events of PD-1 inhibitors among patients with NSCLC. Risks of bias were assessed by using a revised methodological index for nonrandomized studies (MINORS). Pooled incidences and weighted relative risk (RR) estimate for GI adverse events, the incidence of treatment discontinuation due to GI adverse events was also calculated. To perform the analysis of qualified studies, the model of random effects was used and the inconsistency of studies with the I2 index was investigated. OpenMeta 10.10, Stata 11.0 and RevMan 5.3 software were used for data analysis.ResultsThe research included 15 studies comprising of a total of 3,716 patients. The incidences of all-grade GI symptoms were: diarrhea 8.6% (95% CI: 6.6–10.6%), nausea 9.2% (95% CI: 7.3–11.0%), vomiting 3.2% (95% CI: 1.9–4.5%), constipation 2.8% (95% CI: 1.8–3.9%), colitis 0.7% (95% CI: 0.4–1.1%), stomatitis (95% CI: 1.0–2.7%), and decreased appetite 10.0% (95% CI: 8.3–11.7%). Therapy using PD-1 inhibitors was discontinued in 2.5% (95% CI: 0.0–5.1%) of patients with nausea, in 3.0% (95% CI: 0.7–5.3%) of those with diarrhea, and in 45.7% (95% CI: 20.6–70.7%) of patients with colitis. Compared with chemotherapy, the use of PD-1 inhibitors showed significant increase in the occurrence of grade 1–4 colitis (RR =3.90, 95% CI: 1.41–10.81, P=0.009) and grade 3–4 colitis (RR =3.76, 95% CI: 1.07–13.26, P=0.04).DiscussionThis meta-analysis provides a reliable estimate of the incidences of GI adverse events among NSCLC patients. Especially when colitis does occur, it often results in therapy discontinuation. Use of PD-1 inhibitors led to a higher incidence of colitis as compared to the use of chemotherapy.

Real-world analysis of clinicopathological characteristics, survival rates, and prognostic factors in patients with melanoma brain metastases in China.

We aimed to establish the clinicopathological characteristics and prognostic factors of patients with melanoma brain metastases (MBM) in the East Asian population. Overall survival (OS) and intracranial progression-free survival (PFS) were evaluated by Kaplan-Meier analysis. Cox regression analyses were used to determine prognostic factors associated with intracranial PFS and OS. Between July 2007 and December 2019, 431 patients diagnosed with MBM were enrolled. Mucosal subtype (p = 0.013), LDH level (p = 0.014), the number of MBM ≥ 4 (p = 0.02), local treatment (p < 0.0001) and the use of PD-1 inhibitors (p < 0.0001) were independent prognostic factors for intracranial PFS. Mucosal subtype (p = 0.022), LDH level (p = 0.005), no extracranial metastasis (p = 0.01), concurrent liver metastasis (p = 0.004), local treatment (p = 0.001) and the use of PD-1 inhibitors (p < 0.0001) were independent prognostic factors for OS. Mucosal subtype brain metastases had a poor response to PD-1 inhibitors (p = 0.007), with a shorter intracranial PFS than other subtypes. In BRAF mutation patients with MBM, the first-line BRAF/MEK inhibitor therapy group had an advantage in OS compared to the first-line anti-PD-1 therapy group (p = 0.043). Our findings depict clinical characteristics and prognostic factors of MBM in the East Asian population, suggesting the mucosal subtype as an adverse prognostic and predictive factor for patients with MBM. For BRAF mutation patients with MBM, first-line BRAF/MEK inhibitor therapy may bring a potential survival benefit compared to first-line anti-PD-1 therapy.

Nivolumab in Primary CNS Lymphoma and Primary Testicular Lymphoma with CNS Involvement: Single Center Experience

Background.Most patients with primary CNS lymphoma (PCNSL), an aggressive extranodal lymphoma confined to the CNS, have a poor prognosis in spite of development of chemotherapy regimens. First-line treatment consists of high-dose methotrexate-based (HD-MTX) regimen followed by consolidation with autologous stem cell transplantation or whole brain radiotherapy. Given that this tumor manifests predominantly in older patients with median age of 65 years, many patients are unable to tolerate intensive chemotherapy. Moreover, most patients eventually present with relapsed or refractory (r/r) disease. Relapse or refractory (r/r) PCNSL has a poor prognosis with median overall survival not exceeding 3.5 months (Langner-Lemercier et al, 2016) and these patients should be offered a clinical trial whenever possible. These groups are in need of safe, tolerable and effective therapeutic approaches. Primary testicular lymphoma (PTL) shares biological and clinical similarities with PCNSL and often present with CNS involvement. Such patients are also in need of new approaches, especially if they are refractory or not suitable to HD-MTX. Given high PD-1/PD-L1 expression in tumor microenvironment (Berghoff, 2014), immune checkpoint inhibitors were successfully tested in r/r PCNSL and PTL setting. However, data are still scarce and limited to case series (Nayak et al., 2017; Graber et al. 2020). Here we present Pavlov University experience of the treatment of PCNSL and PTL with CNS involvement with PD-1 inhibitor nivolumab. Methods.Eight patients, 2 men and 6 women, with PCNSL and one patient with PTL with CNS involvement treated at the Pavlov University between 2017 and 2020 were included into analysis. Median age at a diagnosis was 62 (28-66) years. Two patients (22%) had ECOG score 3-4 and therefore could not be considered for intensive MTX containing frontline treatment. In all of the cases the tumor histological type was diffuse large B-cell lymphoma. All patients had parenchymal involvement: 7 patients had multifocal disease; deep structures were involved in 2 patients. One patient had leptomeningeal involvement. Nivolumab was used in a first-line setting in 2 patients (22%). In 7 (78%) patients with relapsed/refractory disease, the median number of treatment lines prior to nivolumab was 1 (1-7). Nivolumab was given every 2 weeks in the 100 mg dose. Adverse events were defined according to NCI CTC-AE 5.0. Results.At the time of analysis, the median follow-up was 18 (3-44) months. Median number of nivolumab cycles was 10 (2-23). Seven (78%) patients had an objective response: complete response in 3 patients (33.3%) and partial response in 4 patients (44.4%). Two patients (22.2%) were refractory to treatment. Two-year overall survival (OS) was 44% with median OS of 12 months. Two-year progression-free survival (PFS) was 26% with median of PFS 12 months. Оne responder had a moderate increase of tumor volume on MRI after two months of therapy followed by complete disappearance of brain lesions on sequential imaging at 4 months after treatment initiation. Nivolumab therapy appeared safe with only one patient (11%) having severe adverse event, namely grade 3 alanine aminotransferase and aspartate aminotransferase increase. Conclusion.Nivolumab appears to be safe and effective therapy in PCNSL and PTL with CNS involvement both in first-line and r/r setting. However, in our cohort majority of patients relapsed that suggest that consolidation therapy after remission induction with nivolumab may be crucial for long-term remissions. We also demonstrate that pseudoprogression might be also observed in PCNSL during immunotherapy. Large-scale trials are needed to generate strong evidence for the use of PD-1 inhibitors in PCNSL. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Nivolumab is an anti-PD-1 inhibitor approved for classical Hodgkin lymphoma. There is early clinical data suggesting the efficiency of nivolumab in PCNS lymphoma (Nayak, 2017)